Recent advances in our understanding of neuroendocrine mediators in CFS have raised more questions than answers. Certainly two areas of research stand out and are intertwined: the biology of orthostatic hypotension and the biology of reactivity. Several novel observations are made in this Center application and the four projects will complement each other in a way that, like pieces of a puzzle, bring the overall picture and understanding of CFS into clearer focus. Project I examines autonomic mechanisms that would lead to the low RBC mass as well as the potential for CFS associated cytokines to inhibition erythropoietin production. This leads to a study of RBC mass expansion vs. volume expansion vs. placebo to further delineate our understanding of renal hemodynamics. Project 3 uses the blood volume manipulation to study mechanisms of autonomic and cardiovascular interactions in CFS, and pools data with Project I for a complete picture of this shared study population. Project 2 also manipulates the biology of CFS by modifying the stress response through a cognitive behavioral stress management paradigm, and evaluating its impact on potential mediators of the illness, such as immune function and inflammatory cytokine production. Project 4 capitalizes on the availability of pre intervention post intervention samples to look at mechanisms of natural killer cell dysfunction in CFS, including the role of stress hormones (catecholamines, cortisol) and inflammatory cytokines (TNF-(x) on NK cell function at the molecular level. These projects will each be supported by administrative, health, psychosocial, and laboratory assessment core units.